Advances in identifying women at risk of breast cancer and in treating the disease

Epidemiological studies have identified risk factors for breast cancer. The majority of these are related to estrogen exposure, such as early menarche, late menopause, and use of oral contraceptives and hormone replacement therapy. More recently, part of the reason for familial breast cancer has been explained. In families with multiple breast and/or ovarian cancers there is likely to be mutations in the cell‐cycle control/DNA repair genes BRCA‐1, BRCA‐2 and p53. It is now routine in major centres to test for mutations. When found, preventive measures such as prophylactic mastectomy can be discussed with women. About 5–10% of breast cancer is caused by gene mutation. We do not know the initiating factors in the remainder but we know that a large proportion are related to estrogen, which increases proliferation of normal breast epithelial cells, thus increasing the chances of carcinogenesis, and also promotes proliferation of the altered cell afterwards. The importance of estrogen has been translated into therapy, first by ovarian ablation and in recent years by antiestrogens and, in post menopausal women, the aromatase inhibitors, which lower serum estrogen concentrations. Antiestrogens (e.g., tamoxifen) were shown to be effective for the treatment of advanced breast cancer over thirty years ago. This led to their use after surgery. When given for five years, deaths are reduced by 10–20%. Together with early diagnosis and mammographic screening it is likely that tamoxifen has contributed to the 30% reduction in breast cancer deaths in the UK. Now tamoxifen is used to prevent breast cancer in women at risk. An American study (NSABP P1) of 14 000 women showed that those randomized to tamoxifen had 50% fewer invasive and in‐situ cancers compared with controls given placebo. If this result is replicated in the UK trial (IBIS I), tamoxifen may be more widely used for women at risk. Similar reductions in breast cancer risk were seen in a study using the antiestrogen raloxifene, which has the advantage of not causing endometrial stimulation. Tumours which arise in women given preventative antiestrogens are mostly estrogen receptor negative. In the future we need to find how to prevent these and also to evaluate the preventative effects of lifestyle changes, such as weight loss and increased physical activity. Copyright © 2001 John Wiley & Sons, Ltd.